Some drugs are not stable by themselves or in an acid environment, and require an alkaline environment. In addition, such drugs may possess insufficient solubility and require the use of buffers to obtain complete solubilization prior to processing by conventional wet granulation methods. Furthermore, the buffer can increase the thermal stability of the drug formulation during the drying step of the granulation process.
For example, estropipate is an estrogenic substance (piperazine estrone sulfate) indicated for the treatment of estroqen deficiency in females. Estropipate is unstable in an acid environment or when combined with lactose which is considered an inert pharmaceutical excipient. Excess piperazine has been used to provide an alkaline environment for stabilizing estropipate tablet dosage forms. The excess piperazine also ensures solubilization of the estrone sulfate in the granulating media to ensure a uniform distribution of the drug during the wet granulation process.
A disadvantage of utilizing piperazine is that it is volatile and susceptible to loss when utilizing vacuum drying, which because of environmental considerations is the preferred method of processing granulations containing potent drugs.
Another disadvantage of piperazine is that it is a strong base and may have an adverse effect on excipients used with estropipate. For example, lactose discolors and emits a carmelized odor in the presence of piperazine.